Gross Motor Function Disorders in Patients with Alternating Hemiplegia of Childhood

Abstract Background Alternating hemiplegia of Childhood (AHC) is a rare disease manifested by transient episodes of hemiplegia and other neurological disorders. Delayed motor development has been reported in patients with AHC, but detailed features of the motor impairment have not been described so far. Aim The aim of the study was to evaluate gross motor function between attacks in a group of Polish patients with AHC. Materials and methods The interictal gross motor function was assessed using the Gross Motor Function AHC scale, which consisted of 41 motor tasks. The study group consisted of 10 patients with AHC older than 2 years of age. The control group consisted of 30 age- and gender-matched subjects. The results achieved in each of the 41 tasks by the study subjects were compared to the results obtained with controls using the non-parametric Mann–Whitney U-test. In tasks 38–41, mean times were compared between the study subjects and controls. Results The study revealed gross motor function impairment in patients with AHC. The greatest differences compared to controls concerned such skills as standing on toes, walking on toes, walking on heels, as well as running and hopping on one leg and on alternate legs. Significant impairment of the motor function of the upper limbs was also found. Conclusions The study confirmed motor function impairment between attacks in patients with AHC. The study findings may indicate the need to introduce individualised physiotherapy management of patients with AHC.


Introduction
Alternating hemiplegia of childhood (AHC) is a rare neurological disease characterised by recurrent hemiplegic attacks and other paroxysmal symptoms, abolished with sleep. The incidence is estimated at 1 per 1,000,000 births (1). AHC was first described by Verret and Steele in 1971 (2). Most cases of AHC are attributed to de novo mutations in the ATP1A3 gene coding for alpha-3 catalytic subunit of the Na+/ K(+)-ATPase (3)(4)(5). Paroxysmal symptoms include episodes of hemiplegia, bilateral hemiplegia, quadriplegia, dystonia, tonic spells, seizures and abnormal eye movements (5)(6)(7)(8). Also observed are respiratory difficulty, dysarthria, dysphagia, facial dyskinesia or athetosis, as well as autonomic disturbances their carers expressed their wish to participate in the study. All of the subjects were members of the Polish Association for persons with AHC (AHC-PL). Two children below 2 years of age were not included in the detailed assessment of gross motor function because of their young age, and two patients were excluded from the study due to an ongoing hemiplegic attack. Ultimately, the study was completed by 10 subjects (four females and six males) >2 years of age. Mutations of ATP1A3 were identified in seven subjects. The information on age, height and weight of the study patients, as well as that of the age-and gender-matched controls, is presented in Table 1.
The study consisted of two parts. The subjects with diagnosed AHC and/or their carers first completed a questionnaire providing personal details and history of the disease, and next, the gross motor function was assessed. AHC patients and/or their carers reported typical signs, such as plegic attacks, tonic/dystonic attacks, nystagmus, deviation of the eyes, episodic respiratory difficulties and episodic autonomic disturbances. The plegic attacks occurred from a few to 20-30 times a month and lasted from a few minutes to several days. A detailed list of signs and symptoms, frequency and duration of the attacks in individual study subjects is presented in Table 2. Gross motor function was assessed using the Gross Motor Function AHC (GMF AHC) scale proposed by the authors, comprising 41 motor tasks ranked by order of appearance of motor skills in human motor development ( Table S1). The GMF AHC scale was based on various published motor function scales, mainly on the Hammersmith Functional Motor Scale -Expanded (HFMSE) and the Gross Motor Function Measure (GMFM), and it included other motor tasks proposed by the authors of the study and which were selected after appropriate pilot studies. The GMF describe the disease-specific motor deficits between attacks. The results of the study may allow the design of a dedicated physiotherapy programme for patients with AHC.

Materials and Methods
The study was conducted from November 2014 until the end of May 2015. Contact with the patients was facilitated by the Polish Association for Persons with AHC (AHC-PL), which is a nongovernmental, not-for-profit and support organisation promoting the interests of and acting on behalf of patients with AHC. The subjects were included in the study when AHC was diagnosed by a neurologist or geneticist based on the Aicardi criteria (13). To qualify for a detailed assessment of gross motor capabilities, the subject had to be >2 years of age. The exclusion criteria included a hemiplegic attack during the study or feeling unwell, which made administration of the tests impossible. A control group was established for comparison with gross motor function assessments in AHC patients. For each study subject, three age (+ 6 months)-and gender-matched controls were randomly selected, i.e. a total of 30 controls. The exclusion criteria for controls included the following: participation in competitive sports; post-injury status or surgical operation within the past 12 months; or feeling unwell, which made completing the study impossible. The parents of the children and the adults participating in the study were informed about its aims, and they signed the consent to participate in the study and publish data form.   The GMFM was originally designed to assess gross motor function in children with cerebral palsy (17). It has also been used and validated in children with other diseases associated with significant motor impairment (18)(19)(20). The authors used the following sub-tests from GMFM: 24. Walks forward; 28. Runs.
AHC scale used 23 items from the HFMSE and 2 items from the GMFM. Because of the differences in age and motor function status among the patients, after an initial assessment of some of them, 16 new motor tasks were added.
The HFMS was originally developed to assess function in non-ambulant children with spinal muscular atrophy. The scale was later modified, extended (HFMSE) and validated (14)(15)(16). Authors used the following sub-tests from HFMSE: 1. Lifts head from supine position; 2. Moves from lying to sitting position; 3. Duration of sitting; 4. Duration of long sitting; 5. Places right hand on head while sitting, hand touching the head above the level of ears; 6. Places left hand on head while sitting, hand touching the head above the level of ears; 7. Places two hands on head while sitting, hands touching the head above the level of ears; 8. Moves from sitting to lying

Discussion
Studies of AHC are relatively recent and, to date, cases of patients from a number of countries have been reported (10,12,(21)(22)(23)(24)(25)(26). The aim of the present study was to provide detailed characteristics of gross motor dysfunction in AHC patients. To the best of our knowledge, to date, no other such study has been performed.
There are no available tools to assess gross motor function in AHC or to compare gross motor function in subjects who vary greatly in age. The motor tasks included in the Gross Motor Function AHC scale developed for the purpose of the present study allow the assessment of motor function in particular body parts and, as a result, a detailed description of the motor dysfunction in each subject. The Gross Motor Function AHC is based on items of the HFMSE and the GMFM, to which new sub-tests have been added. The advantage of the GMF AHC is its ability to assess the subject's performance in different positions, from lying prone and supine to standing, during both static and dynamic activities. However, the scoring system does not assess the quality and precision of the movements, which should be addressed in further studies. We found gross motor impairment in AHC subjects, in agreement with the reports from other authors, who observed delayed development in most individuals with AHC (5,10). In our study, AHC subjects achieved the worst results in the following tasks: standing and walking on toes, walking on heels, running, hopping on one leg and hopping on alternate legs. Walking abnormalities in AHC were also noted in other published studies (5). Kirshenbaum et al. (27) studied mice with mutations in the gene responsible for AHC. The animals had less-stable gait, walked with shorter steps and had poorer postural stability than wild-type mice (27).
In the present study, two subjects aged 2.5 and 3.5 years were not able to walk independently.
The results of the present study mostly indicate impaired control of the muscles producing plantar and dorsal flexion of the foot, stabilising muscles of the foot, as well as muscles straightening the knee and hip joints, which are active during hopping, walking and running. Additionally, the test results suggest impaired coordination and fluidity of movement, with a narrow base of support. Tests performed in a lying position did not reveal any dysfunction of trunk muscles. However, significantly impaired function of the upper limbs was observed during catching and throwing. Such a pattern of muscle function abnormalities is consistent with disturbances in consecutive phases of development and indicates generally delayed development. Interestingly, inability to perform alternate movements of the trunk and extremities was observed in all study patients. Our findings allow the The tests were carried out on patients in the lying, sitting and standing positions. Tasks 1-37 could score 0, 1 or 2 points (0= task not performed; 1= task partially performed; 2= task normally performed), while in tasks 38-41, the time it took the subject to perform the task was measured. Tasks 38-41 had to be performed in triplicate up to 15 seconds in duration, and the best result was recorded. Instructions for each motor task were given to the subject verbally, followed by a demonstration by the investigator.
The results for the study subjects were analysed using the SPSS software. The results achieved in each of the 41 tasks by the study subjects were compared to the results for controls using the non-parametric Mann-Whitney U-test. In tasks 38-41, the mean times were compared between the study subjects and controls. The results were considered statistically significant at p<0.05.

Results
Tests for gross motor function in subjects aged 2-30 years found statistically significant differences between the study group and controls in 22 tasks (

Conclusion
Gross motor impairment is observed in patients with AHC between attacks. The present study mostly indicates impaired control of the muscles responsible for the functioning of the lower extremities. The study findings may indicate the need to introduce individualised physiotherapy management of patients with AHC, tailored to their motor development, but this requires further research.